Traumatic brain injury (TBI) afflicts almost 500,000 Americans a year, but unfortunately, existing treatments have only minimal ability to prevent secondary brain damage accompanying traumatic brain injury. Epidemiological data that suggests that women fare better then men following TBI, but the basis for this difference is not understood. It is likely that action of female sex hormones, particularly estrogen, may have significant effects on the progression of brain injury, and recent data from our laboratory suggests that estrogen has potent anti-inflammatory properties that could account for its ability to attenuate traumatic brain injury. In particular, data indicates that estrogen is able to decrease oxidative burst activity and subsequent redox-based inflammatory signaling in glial cells, thereby attenuating neurotoxic brain inflammation. Therefore, it is proposed that estrogen acts to preserve brain function following TBI by decreasing both blood-brain barrier (BBB) breech and neuronal injury, and that these distinct endpoints are mediated by a single mechanism: modulation of the glial oxidative burst. Specific Aim 1 will test the hypothesis that estrogen is able to significantly attenuate oxidative burst activity in astrocytes, microglial cells, and endothelial cells both in vitro and in vivo, and will determine the role of estrogen receptors in this process through use of estrogen receptor knockout mice. Specific Aim 2 will test the hypothesis that by directly interfering with oxidative burst activity, estrogen blocks the release of matrix metalloproteinases and thus preserves blood-brain barrier integrity in mice following traumatic brain injury. Specific Aim 3 will build upon these studies by testing the hypothesis that by decreasing oxidative burst activity and redox signaling, estrogen blocks the formation of neurotoxic inflammatory mediators (excitotoxins and cytokines), culminating in decreased injury and increased recovery following traumatic brain injury. Completion of these studies will result in a thorough understanding of the mechanisms of estrogen-mediated neuroprotection in TBI and could highlight a novel target for therapeutic intervention following brain trauma in both women and men.